Amelioration of experimental autoimmune encephalomyelitis with Anti-OX40 ligand monoclonal antibody: A critical role for OX40 ligand in migration, but not development, of pathogenic T cells

OX40 (CD134) and its ligand (OX40L) have been implicated in T cell activati on and migration. In this study, we examined the contribution of these mole cules to the pathogenesis of experimental autoimmune encephalomyelitis (EAE ) by administering a neutralizing mAb against murine OX40L (RM134L) to prot eolipid protein (139-151) peptide-induced EAE in SJL mice, Administration o f RM134L effectively ameliorated the disease in both actively induced and a doptively transferred EAE models. Histological examination showed that the RM134L treatment greatly reduced mononuclear cell infiltration into the spi nal cord. The RM134L treatment did not inhibit the development of pathogeni c T cells, given that proliferative response and IFN-gamma production by dr aining lymph node cells were not reduced or rather enhanced upon restimulat ion with proteolipid protein ( 139-151) in vitro, and these cells effective ly transferred EAE to naive SJL mice. Flow cytometric analyses showed that the RM134L treatment inhibited the accumulation of OX40-expressing CD4(+) T cells and the migration of adoptively transferred CD4(+) T cells in the sp inal cord. Immunohistochemical staining showed that OX40L was most prominen tly expressed on endothelial cells in the inflamed spinal cord. These resul ts suggest that the OX40/OX40L interaction plays a critical role fur the mi gration of pathogenic T cells into the CNS in the pathogenesis of EAE.